Chemokines, also referred to as intercrine cytokines, are a subfamily of structurally and functionally related cytokines. These molecules are 8-14 kd in size. In general chemokines exhibit 20% to 75% homology at the amino acid level and are characterized by four conserved cysteine residues that form two disulfide bonds. Based on the arrangement of the first two cysteine residues, chemokines have been classified into two subfamilies, alpha and beta. In the alpha subfamily, the first two cysteines are separated by one amino acid and hence are referred to as the “CXC” subfamily. In the beta subfamily, the two cysteines are in an adjacent position and are, therefore, referred to as the “CC” subfamily. Recently, a new chemokine-like molecule, lymphotactin/SCM-1, which lacks the first and the third conserved cysteine residues, has been isolated and may represent a third subfamily (Kelner et al., Science 266:1395-1399 (1994)).
The intercrine cytokines exhibit a wide variety of functions. A hallmark feature is their ability to elicit chemotactic migration of distinct cell types, including monocytes, neutrophils, T lymphocytes, basophils and fibroblasts. Many chemokines have proinflammatory activity and are involved in multiple steps during an inflammatory reaction. These activities include stimulation of histamine release, lysosomal enzyme and leukotriene release, increased adherence of target immune cells to endothelial cells, enhanced binding of complement proteins, induced expression of granulocyte adhesion molecules and complement receptors, and respiratory burst. In addition to their involvement in inflammation, certain chemokines have been shown to exhibit other activities. For example, macrophage inflammatory protein I (MIP-1) is able to suppress hematopoietic stem cell proliferation, platelet factor-4 (PF-4) is a potent inhibitor of endothelial cell growth, Interleukin-8 (IL-8) promotes proliferation of keratinocytes, and GRO is an autocrine growth factor for melanoma cells.
Chemokine beta-4 (CK-β4; also known as CCL20, MIP-3α, and LARC) represents a novel, divergent beta-chemokine. CK-β4 contains the four cysteine residues characteristic of CC chemokines and shows sequence similarity with other human CC chemokines. The highest homology (28%) is with chemoline MIP-1β (Hieshima, et al. J. Biol. Chem. 272:5846-5853 (1997)). CK-β4 is expressed preferentially in lymphocytes and monocytes, and its expression is markedly upregulated by mediators of inflammation such as tumor necrosis factor (TNF) and lipopolysaccharide. The CK-β4 gene has been mapped between the bands of q33 and q37 of chromosome 2 (Ibid.). The only receptor identified for CK-β4, thus far, is CCR6 (Greaves, et al., J. Exp. Med 186:837-844).
The immune cells that are responsive to the chemokines have a vast number of in vivo functions and therefore their regulation by such chemokines is an important area in the treatment of disease. For example, eosinophils destroy parasites to lessen parasitic infection. Eosinophils are also responsible for chronic inflammation in the airways of the respiratory system. Macrophages are responsible for suppressing tumor formation in vertebrates. Further, basophils release histamine, which may play an important role in allergic inflammation.
Accordingly, promoting and inhibiting such cells, has wide therapeutic application. There is a clear need, therefore, for identification and characterization of compositions, such as antibodies, that influence the biological activity of chemokines, both normally and in disease states. In particular, there is a need to isolate and characterize antibodies that modulate the biological activities of chemokine beta-4 for the treatment of proliferative disorders, as well as immune system diseases and disorders including autoimmune disease, inflammatory disorders, immunodeficiencies, infections, HIV, arthritis, allergy, psoriasis, dermatitis, and inflammatory bowel disease.